Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma (CALGB 500104)

Gajewski, Salama, Niedzwiecki Donna, Johnson Jeffrey, Linette Gerald, Bucher Cynthia, Blaskovich, Sebti, Haluska Frank, The

Description

Multiple farnesylated proteins are involved in signal transduction in cancer. Farnesyltransferase inhibitors (FTIs) have been developed as a strategy to inhibit the function of these proteins. As FTIs inhibit proliferation of melanoma cell lines, we undertook a study to assess the impact of a FTI in advanced melanoma. As farnesylated proteins are also important for T cell activation, measurement of effects on T cell function was also pursued. Methods A 3-stage trial design was developed with a maximum of 40 patients and early stopping if there were no responders in the first 14, or fewer than 2 responders in the first 28 patients. Eligibility included performance status of 0–1, no prior chemotherapy, at most 1 prior immunotherapy, no brain metastases, and presence of at least 2 cutaneous lesions amenable to biopsy. R115777 was administered twice per day for 21 days of a 28-day cycle. Patients were evaluated every 2 cycles by RECIST. Blood and tumor were analyzed pre-treatment and during week 7. Results Fourteen patients were enrolled. Two patients had grade 3 toxicities, which included myelosuppression, nausea/vomiting, elevated BUN, and anorexia. There were no clinical responses. All patients analyzed showed potent inhibition of FT activity (85-98%) in tumor tissue; inhibition of phosphorylated ERK and Akt was also observed. T cells showed evidence of FT inhibition and diminished IFN-γ production. Conclusions Despite potent target inhibition, R115777 showed no evidence of clinical activity in this cohort of melanoma patients. Inhibition of T cell function by FTIs has potential clinical implications. Clinicaltrials.gov number NCT00060125

Sujets

• Melanoma
• Farnesyltransferase inhibitor
• Tipifarnib
• RAS
• T cell

Informations

• Publié par: biomed
• Publié le: 01 janvier 2012
• Nombre de lectures: 8
• Langue: English

Extrait

Gajewskiet al. Journal of Translational Medicine2012,10:246 http://www.translationalmedicine.com/content/10/1/246

R E S E A R C HOpen Access Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma (CALGB 500104) 1* 23 34 5 Thomas F Gajewski, April KS Salama , Donna Niedzwiecki , Jeffrey Johnson , Gerald Linette , Cynthia Bucher , 5 56 Michelle A Blaskovich , Said M Sebti , Frank Haluska for the Cancer and Leukemia Group B

Abstract Background:Multiple farnesylated proteins are involved in signal transduction in cancer. Farnesyltransferase inhibitors (FTIs) have been developed as a strategy to inhibit the function of these proteins. As FTIs inhibit proliferation of melanoma cell lines, we undertook a study to assess the impact of a FTI in advanced melanoma. As farnesylated proteins are also important for T cell activation, measurement of effects on T cell function was also pursued. Methods:A 3stage trial design was developed with a maximum of 40 patients and early stopping if there were no responders in the first 14, or fewer than 2 responders in the first 28 patients. Eligibility included performance status of 0–1, no prior chemotherapy, at most 1 prior immunotherapy, no brain metastases, and presence of at least 2 cutaneous lesions amenable to biopsy. R115777 was administered twice per day for 21 days of a 28day cycle. Patients were evaluated every 2 cycles by RECIST. Blood and tumor were analyzed pretreatment and during week 7. Results:Fourteen patients were enrolled. Two patients had grade 3 toxicities, which included myelosuppression, nausea/vomiting, elevated BUN, and anorexia. There were no clinical responses. All patients analyzed showed potent inhibition of FT activity (8598%) in tumor tissue; inhibition of phosphorylated ERK and Akt was also observed. T cells showed evidence of FT inhibition and diminished IFNγproduction. Conclusions:Despite potent target inhibition, R115777 showed no evidence of clinical activity in this cohort of melanoma patients. Inhibition of T cell function by FTIs has potential clinical implications. Clinicaltrials.gov number NCT00060125 Keywords:Melanoma, Farnesyltransferase inhibitor, Tipifarnib, R11577, RAS, T cell activation

Background Metastatic melanoma is difficult to treat and it is only re cently that therapy has been shown to have an impact on overall survival [13]. DTIC/dacarbazine has been shown in contemporary studies to provide tumor responses in less than 15% of patients, with a median response duration of 3–4 months [4,5]. Combination therapies may increase response rates, but without improvement in survival [6]. High dose interleukin2 and ipilimumab benefit the mi nority of patients, albeit with a subset of patients experien cing durable responses [1,7,8]. Although many patients with BRAFmutated melanoma initially respond to

* Correspondence: [e-mail] 1 The University of Chicago, Section of Hematology/Oncology, 5841 S. Maryland Ave., MC2115, Chicago, IL 60637, USA Full list of author information is available at the end of the article

vemurafenib, the only other agent approved by the FDA for this disease, most will ultimately relapse [2]. Thus, while significant advances in both immune based and mo lecularly targeted therapies have been made, survival for many patients with metastatic melanoma remains poor. New therapies are still needed for this disease, and the testing of new agents is being driven by an increasing knowledge of melanoma biology. The vast majority of melanomas have activating muta tions in signaling proteins involved in the RAS pathway. Mutations in RAS occur in around 15% of melanomas [9,10]. In addition, frequent mutations in downstream RAS effectors have been reported, the most common of which is BRAF which has been reported to be mutated in approxi mately 50% of cases [1113]. Mutated BRAF can be

© 2012 Gajewski et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.